1. Field of the Invention
The present invention relates to antiviral agents, particularly to nucleoside-based antiviral drugs, and specifically to a series of 4'-azido- and 4'-methoxy-substituted nucleosides. The invention is also directed to formulations and methods for treating viral infections in a mammal, as well as to methods of making the subject compounds.
2. Background Information
Viruses have lone been known to be the cause of some of the most costly, troublesome and devastating infections to man. In recent years, this pattern has been underscored by the onset of Acquired Immune Deficiency Syndrome (AIDS), which has been found to be the result of infection by the human immunodeficiency virus (HIV).
Various active agents have been proposed for the treatment of viruses such as AIDS. Typically, these active agents have suffered from a disadvantageous therapeutic index, i.e., the ratio of activity to toxicity (in other words, their beneficial effect was outweighted by their toxic nature).
For example, the drug AZT (3'-azidothymidine) is described in European Patent Application 86307071.0; it is presently used for treatment of AIDS. It is not, however, a cure for the disease. AZT is also fairly toxic to the bone marrow, requiring patients under treatment to receive frequent blood transfusions, and although their disease symptoms are diminished and life is prolonged, AIDS related death is still considered inevitable.
Another example is the drug DDC (2',3'-dideoxycytidine), as described in PCT/US86/01626, having an international filing date of Aug. 8, 1986, claiming priority from U.S. Ser. No. 769,017, now abandoned, filed Aug. 26, 1985. This drug is currently under investigation for the treatment of HIV infection. It is more potent than AZT, but, it is also very toxic, leading often to severe peripheral neuropathy.
4'-Substituted nucleosides have been described previously [see Ann. N.Y. Acad. Sci., 255, 151 (1975)]. More particularly, various 4'-methoxypurine and 4'-methoxypyrimidine ribonucleosides and 4'-azidocytidine have been synthesized and screened for their antiviral activity, but, have not shown any usefulness in this regard. For example, 4'-azidocytidine is cytotoxic and devoid of anti-HIV activity.
5-Chloro-substituted derivatives of 2',3'-didehydro-2',3'-dideoxyuridine, 3'-fluoro-2',3'-dideoxyuridine and 3'-azido-2',3'-dideoxyuridine have been described previously [see Biochemical Pharmacology, Vol 38, No. 6, pp 869-74 (1989)]. Preliminary results there report that 5-chloro-substituted-3'-fluoro-2',3'-dideoxyuridine and 5-chloro-substituted-3'-azido-2',3'-dideoxyuridine exhibit potent antiviral activity, however, further studies are required to assess their therapeutic potential.
It has remained desired to provide antiviral active agents having a high therapeutic index, such as the compounds of the present invention.